Effects Of Apigenin Research Articles

Antimicrobial synergistic effects of apigenin, (-)-epigallocatechin-3-gallate, myricetin and luteolin in combination with some antibiotics.

Antimicrobial resistance, which is considered one of the most important problems of the 21 st century, brings many problems with it, such as increasing mortality rates and treatment costs. Difficulties in the treatment of infections caused by resistant microorganisms have led to the search and need for new antimicrobials or new molecules that interact synergistically with antimicrobials. The aim of this study is to investigate whether various flavonoids have synergistic effects with some antibiotics. During this study, standard bacterial strains Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 700603, Pseudomonas aeruginosa ATCC 9027, Staphylococcus aureus ATCC 29213 and Staphylococcus aureus ATCC 43300 were used. Minimal inhibitory concentrations of all antibiotics and flavonoids were found by the broth microdilution method. Interactions between antibiotics and flavonoids were then determined by using the checkerboard method. Interactions between antibiotics and flavonoids were evaluated according to the FIC index (ΣFIC) results. According to the results of the microdilution test, the bacterial strains used in this study (except for MRSA) were generally sensitive to antibiotics. Interaction study results showed promising results regarding the synergistic interactions of antibiotics with flavonoids. Epigallocatechin gallate and luteolin especially showed synergistic interaction with antibiotics in many microorganisms. It was found that myricetin showed synergistic interaction only with levofloxacin. Likewise, it was detected that apigenin had limited synergistic interaction with antibiotics. The obtained results highlight that flavonoids may be a useful tool in overcoming antibiotic resistance.

Apigenin alleviates oxidative stress-induced myocardial injury by regulating SIRT1 signaling pathway

Apigenin is a natural flavonoid which is widely found in vegetables and fruits. However, the mechanism of apigenin in oxidative stress-induced myocardial injury has not been fully elucidated. We established an isoproterenol (Iso)-induced myocardial injury mouse model and a hypoxia/reoxygenation (H/R)-induced H9c2 cell injury model, followed by pretreatment with apigenin to explore its protective effects. Apigenin can significantly alleviate isoproterenol-induced oxidative stress, cell apoptosis and myocardial remodeling in vivo. Apigenin pretreatment can also significantly improve cardiomyocyte morphology, decrease H/R induced oxidative stress, and attenuate cell apoptosis and inflammation in vitro. Further mechanism study revealed that apigenin treatment reversed isoprenaline and H/R-induced decrease of Sirtuin1 (SIRT1). Molecular docking results proved that apigenin can form hydrogen bond with 230 Glu, a key site of SIRT1 activation, indicating that apigenin is an agonist of SIRT1. Moreover, SIRT1 knockdown by siRNA significantly reversed the protective effect of apigenin in H/R-induced myocardial injury. In conclusion, apigenin protects cardiomyocyte function from oxidative stress-induced myocardial injury by modulating SIRT1 signaling pathway, which provides a new potential therapeutic natural compound for the clinical treatment of cardiovascular diseases.

An integrated in-silico Pharmaco-BioInformatics approaches to identify synergistic effects of COVID-19 to HIV patients

BackgroundWith high inflammatory states from both COVID-19 and HIV conditions further result in complications. The ongoing confrontation between these two viral infections can be avoided by adopting suitable management measures. PurposeThe aim of this study was to figure out the pharmacological mechanism behind apigenin's role in the synergetic effects of COVID-19 to the progression of HIV patients. MethodWe employed computer-aided methods to uncover similar biological targets and signaling pathways associated with COVID-19 and HIV, along with bioinformatics and network pharmacology techniques to assess the synergetic effects of apigenin on COVID-19 to the progression of HIV, as well as pharmacokinetics analysis to examine apigenin's safety in the human body. ResultStress-responsive, membrane receptor, and induction pathways were mostly involved in gene ontology (GO) pathways, whereas apoptosis and inflammatory pathways were significantly associated in the Kyoto encyclopedia of genes and genomes (KEGG). The top 20 hub genes were detected utilizing the shortest path ranked by degree method and protein-protein interaction (PPI), as well as molecular docking and molecular dynamics simulation were performed, revealing apigenin's strong interaction with hub proteins (MAPK3, RELA, MAPK1, EP300, and AKT1). Moreover, the pharmacokinetic features of apigenin revealed that it is an effective therapeutic agent with minimal adverse effects, for instance, hepatoxicity. ConclusionSynergetic effects of COVID-19 on the progression of HIV may still be a danger to global public health. Consequently, advanced solutions are required to give valid information regarding apigenin as a suitable therapeutic agent for the management of COVID-19 and HIV synergetic effects. However, the findings have yet to be confirmed in patients, suggesting more in vitro and in vivo studies.

Effects of Apigenin on Pharmacokinetics of Dasatinib and Probable Interaction Mechanism.

Dasatinib (DAS), a narrow-therapeutic index drug, Bcr-Abl, and Src family kinases multitarget inhibitor have been approved for chronic myelogenous leukemia (CML) and Ph-positive acute lymphocytic leukemia (Ph+ ALL). Apigenin (APG) has a long history of human usage in food, herbs, health supplements, and traditional medicine, and it poses low risk of damage. The concomitant use of APG containing herbs/foods and traditional medicine may alter the pharmacokinetics of DAS, that probably lead to possible herb-drug interactions. The pharmacokinetic interaction of APG pretreatment with DAS in rat plasma following single and co-oral dosing was successfully deliberated using the UPLC-MS/MS method. The in vivo pharmacokinetics and protein expression of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 demonstrate that APG pretreatment has potential to drastically changed the DAS pharmacokinetics where escalation in the Cmax, AUC(0-t), AUMC(0-inf_obs), T1/2, Tmax, and MRT and reduction in Kel, Vd, and Cl significantly in rats pretreated with APG 40 mg/kg, thus escalating systemic bioavailability and increasing the rate of absorption via modulation of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 protein expression. Therefore, the concomitant consumption of APG containing food or traditional herb with DAS may cause serious life-threatening drug interactions and more systematic clinical study on herb-drug interactions is required, as well as adequate regulation in herbal safety and efficacy.

Effect of apigenin in combination with oxymatrine on non-small cell lung cancer and mechanism

This study explores the effect of apigenin(APG), oxymatrine(OMT), and APG+OMT on the proliferation of non-small cell lung cancer cell lines and the underlying mechanisms. Cell counting kit-8(CCK-8) assay was used to detect the vitality of A549 and NCI-H1975 cells, and colony formation assay to evaluate the colony formation ability of the cells. EdU assay was employed to examine the proliferation of NCI-H1975 cells. RT-qPCR and Western blot were performed to detect the mRNA and protein expression of PLOD2. Molecular docking was carried out to explore the direct action ability and action sites between APG/OMT and PLOD2/EGFR. Western blot was used to study the expression of related proteins in EGFR pathway. The viability of A549 and NCI-H1975 cells was inhibited by APG and APG+OMT at 20, 40, and 80 μmol·L~(-1) in a dose-dependent manner. The colony formation ability of NCI-H1975 cells was significantly suppressed by APG and APG+OMT. The mRNA and protein expression of PLOD2 was significantly inhibited by APG and APG+OMT. In addition, APG and OMT had strong binding activity with PLOD2 and EGFR. In APG and APG+OMT groups, the expression of EGFR and proteins in its downstream signaling pathways was significantly down-regulated. It is concluded that APG in combination with OMT could inhibit non-small lung cancer, and the mechanism may be related to EGFR and its downstream signaling pathways. This study lays a new theoretical basis for the clinical treatment of non-small cell lung cancer with APG in combination with OMT and provides a reference for further research on the anti-tumor mechanism of APG in combination with OMT.

Investigating the mechanism of antiepileptogenic effect of apigenin in kainate temporal lobe epilepsy: possible role of mTOR.

Clarifying the underlying mechanisms of epileptogenesis is important in preventing the progression of chronic epilepsy. In epilepsy, the mTOR (mammalian target of rapamycin) pathway plays a critical role in mediating the mechanism of epileptogenesis. In this study, we investigate whether apigenin can exert antiepileptogenic effects through the inhibition of mTOR in the kainate model of epilepsy. For assessing the antiepileptogenic effect of apigenin in kainic acid (KA)-induced temporal lobe epilepsy (TLE) model, apigenin at a dose of 50mg/kg was administrated by gavage for 6days. An intracranial electroencephalogram (iEEG) was performed to confirm the establishment of status epilepticus. BrdU was used to detect neurogenesis in the CA3, and dentate gyrus and mossy fiber sproutings were assessed by Timm staining. The expression of mTOR was quantified via western blot. We found that apigenin-pretreatment had a significant inhibitory effect on neural cell death, spontaneous seizure spikes, aberrant neurogenesis, mTOR hyperactivity, and aberrant mossy fiber sprouting. Overall, these results suggest that apigenin has an antiepileptogenic effect and may be a useful target for inhibiting mTOR hyperactivity in epilepsy.

Molecular Mechanism of the Role of Apigenin in the Treatment of Hyperlipidemia: A Network Pharmacology Approach.

The therapeutic effect of apigenin (APG) on hyperlipidemia was investigated using network pharmacology combined with molecular docking strategy, and the potential targets of APG in the treatment of hyperlipidemia were explored. Genetic Ontology Biological Process (GOBP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment analysis of common targets were performed. Then, molecular docking was used to predict the binding mode of APG to the target. Finally, Sprague Dawley rats were used to establish a hyperlipidemia model. The expression levels of insulin (INS) and vascular endothelial growth factor A (VEGFA) mRNA in each group were detected by quantitative reverse transcription-polymerase chain reaction. Network pharmacological studies revealed that the role of APG in the treatment of hyperlipidemia was through the regulation of INS, VEGFA, tumor necrosis factor, epidermal growth factor receptor, matrix metalloprotein 9, and other targets, as well as through the regulation of the hypoxia-inducible factor 1 (HIF-1) signaling pathway, fluid shear stress, and atherosclerosis signaling pathways, vascular permeability; APG also participated in the regulation of glucose metabolism and lipid metabolism, and acted on vascular endothelial cells, and regulated vascular tone. Molecular docking showed that APG binds to the target with good efficiency. Experiments showed that after APG treatment, the expression levels of INS and VEGFA mRNA in the model group were significantly decreased (p<0.01). In conclusion, APG has multiple targets and affects pathways involved in the treatment of hyperlipidemia by regulating the HIF-1 signaling pathway, fluid shear stress, and the atherosclerosis pathway.

Apigenin attenuates tetrabromobisphenol A-induced cytotoxicity in neuronal SK-N-MC cells

Tetrabromobisphenol A (TBBPA) is a reactive brominated flame retardant widely used in various industrial and household products. This compound is persistent in the environment and accumulates in living organisms through the food chain, and is toxic to animals and human beings. Studies have shown that TBBPA is toxic to various human cell lines, including neuronal cells. Apigenin is a dietary flavonoid that exhibits various beneficial health effects on biological activities, including antioxidant, anti-inflammatory, and neuroprotective effects. This study investigated the cytoprotective effects of apigenin against TBBPA-mediated cytotoxicity in SK-N-MC cells. Our results demonstrated that treatment of SK-N-MC cells with apigenin increased the cell viability, which was decreased by TBBPA, and reduced apoptosis and autophagy induced by TBBPA. Although we did not observe any change in the levels of IL-1β and nitrite in cultured cells after TBBPA treatment, apigenin was found to decrease the production of these pro-inflammatory mediators. Apigenin decreased the intracellular Ca2+ concentration, NOX4 level, oxidative stress, and mitochondrial membrane potential loss and increased the mitochondrial biogenesis and nuclear Nrf2 levels that were reduced by TBBPA. Finally, apigenin treatment decreased Akt and ERK induction in cells exposed to TBBPA. Based on these results, apigenin could be a promising candidate for designing natural drugs to treat or prevent TBBPA-related neurological disorders.

Apigenin ameliorates non-eosinophilic inflammation, dysregulated immune homeostasis and mitochondria-mediated airway epithelial cell apoptosis in chronic obese asthma via the ROS-ASK1-MAPK pathway

BackgroundObese asthma is one of the important asthma phenotypes that have received wide attention in recent years. Excessive oxidative stress and different inflammatory endotypes may be important reasons for the complex symptoms, frequent aggravation, and resistance to traditional treatments of obese asthma. Apigenin (API), is a flavonoid natural small molecule compound with good anti-inflammatory and antioxidant activity in various diseases and proved to have the potential efficacy to combat obese asthma. MethodsIn vivo, this study fed C57BL/6 J mice with high-fat diets(HFD)for 12 weeks and then stimulated them with OVA for 6 weeks to establish a model of chronic obese asthma, while different doses of oral API or dexamethasone were used for therapeutic interventions. In vitro, this study used HDM to stimulate human bronchial cells (HBEs) to establish the model and intervened with API or Selonsertib (SEL). ResultsThis study clarified that OVAinduced a type of mixed granulocytic asthma with elevated neutrophils and eosinophils in obese male mice fed with long-term HFD, which also exhibited mixed TH17/TH1/TH2 inflammation. Apigenin effectively suppressed this complex inflammation and acted as a regulator of immune homeostasis. Meanwhile, apigenin reduced AHR, inflammatory cell infiltration, airway epithelial cell apoptosis, airway collagen deposition, and lung oxidative stress via the ROS-ASK1-MAPK pathway in an obese asthma mouse model. In vitro, this study found that apigenin altered the binding status of TRAF6 to ASK1, inhibited ASK1 phosphorylation, and protected against ubiquitin-dependent degradation of ASK1, suggesting that ROS-activated ASK1 may be an important target for apigenin to exert anti-inflammatory and anti-apoptotic effects. To further verify the intervention mechanism, this study clarified that apigenin improved cell viability and mitochondrial function and inhibited apoptosis by interfering with the ROS-ASK1-MAPK pathway. ConclusionsThis study demonstrates for the first time the therapeutic effect of apigenin in chronic obese asthma and further clarifies its potential therapeutic targets. In addition, this study clarifies the specificity of chronic obese asthma and provides new options for its treatment.

Immunopotentiation effects of apigenin on NK cell proliferation and killing pancreatic cancer cells.

Apigenin is a kind of flavonoid with many beneficial biological effects. It not only has direct cytotoxicity to tumor cells, but also can boost the antitumor effect of immune cells by modulating immune system. The purpose of this study was to investigate the proliferation of NK cells treated with apigenin and its cytotoxicity to pancreatic cancer cells in vitro, and explore its potential molecular mechanism. In this study, the effect of apigenin on NK cell proliferation and killing pancreatic cancer cells were measured by CCK-8 assay. Perforin, granzyme B (Gran B), CD107a, and NKG2D expressions of NK cells induced with apigenin were detected by flow cytometry (FCM). The mRNA expression of Bcl-2, Bax and protein expression of Bcl-2, Bax, p-ERK, and p-JNK in NK cells were evaluated by qRT-PCR and western blotting analysis, respectively. The results showed that appropriate concentration of apigenin could significantly promote the proliferation of NK cells in vitro and enhance the killing activity of NK cells against pancreatic cancer cells. The expressions of surface antigen NKG2D and intracellular antigen perforin and Gran B of NK cells were upregulated after treating with apigenin. Bcl-2 mRNA expression was increased, while Bax mRNA expression was decreased. Similarly, the expression of Bcl-2, p-JNK, and p-ERK protein was upregulated, and the expression of Bax protein was downregulated. The molecular mechanism of the immunopotentiation effects of apigenin may be that it up-regulates Bcl-2 and down-regulates Bax expression at the gene and protein levels to facilitate NK cell proliferation, and up-regulates the expression of perforin, Gran B, and NKG2D through the activation of JNK and ERK pathways to enhance NK cell cytotoxicity.

Combined effect of apigenin and reduced graphene oxide against Enterococcus faecalis biofilms.

Enterococcus faecalis (E. faecalis) is one of the major microorganisms that causes failure of endodontic treatment. This study aimed to investigate the antibacterial activity of apigenin and its synergistic effect with reduced graphene oxide (RGO) in treating E. faecalis biofilms. The antibacterial activities were characterized by viability analysis including colony forming units and confocal laser scanning microscopy (CLSM) analyses. The effect on biofilm biomass was measured using a crystal violet staining method. Live and dead bacteria bio-volumes were determined by CLSM analysis, and the morphology of E. faecalis biofilm after treatment with apigenin and apigenin + RGO was observed by scanning electron microscopy (SEM). The viability of E. faecalis in biofilms decreased by apigenin treatment in a dose-dependent manner. While apigenin alone did not significantly affect the biofilm biomass, apigenin + RGO reduced the biomass in an apigenin concentration-dependent manner. Likewise, the bio-volume of live bacteria decreased and the bio-volume of dead bacteria increased in apigenin-treated biofilms. According to SEM images, apigenin + RGO-treated samples showed less E. faecalis in biofilms than apigenin-only treated samples. The results suggested that the combined use of apigenin and RGO could be a potential strategy for effective endodontic disinfection.

The Ameliorative Effect of Apigenin or Silymarin as Add-On Therapy to Risperidone on Valproic Acid Induced Autism in Albino Rats: Implication of Oxidative Stress, Apoptosis and Autophagy

The Ameliorative Effect of Apigenin or Silymarin as Add-On Therapy to Risperidone on Valproic Acid Induced Autism in Albino Rats: Implication of Oxidative Stress, Apoptosis and Autophagy

Evaluation of Antimalarial Activity of Ethanolic Extract of Annona muricata L.: An in vivo and an in silico Approach.

In Nigeria, Annona muricata L. has been used to treat a variety of ailments. The mechanism of the antimalarial activity of ethanolic leaf extract of Annona muricata (EEAML) was investigated using both an in vivo and an in silico approach. The experimental mice were divided into five groups: A-F. The mice in groups B-F were inoculated with Plasmodium berghei NK-65 and treated accordingly. Groups A and B are the negative and positive controls (infected and untreated), respectively. Group C received 10 mg/kg chloroquine (standard drug), whereas groups D-F received 100, 200, and 300 mg/kg body weight of the extract orally respectively. The mice were euthanized eight days after infection, and their liver and blood were collected and used in biochemical tests. Molecular docking was performed using the extract's HPLC compounds and Plasmodium falciparum proteins. In the suppressive, prophylactic, and curative tests, there was a significant decrease (p < 0.05) in parasitemia levels in groups treated with the extract compared to the positive control and standard drug. When compared to the positive control, there was a significant (p < 0.05) reduction in liver MDA, total cholesterol, and total triglyceride levels. The binding energies of luteolin and apigenin-pfprotein complexes were significantly (p < 0.05) higher compared to their respective references. The anti-plasmodial activity of the extract may result from its hypolipidemic effect, which deprives the parasite of essential lipid molecules needed for parasite growth, as well as from the inhibitory effects of apigenin and luteolin on specific proteins required for the Plasmodium metabolic pathway.

Effect of apigenin on tryptophan metabolic key enzymes expression in lipopolysaccharide-induced microglial cells and its mechanism

[Aims] Flavonoid apigenin (API) has a wide range of biological functions, particularly anti-inflammation. Indoleamine 2,3-dioxygenase (IDO) and 2-Amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD) are important tryptophan metabolic enzymes that play pivotal roles in the production of toxic metabolite quinolinic acid. However, the relationship between inflammation and ACMSD remains unclear. The present study investigated the relationship between inflammation and tryptophan metabolic key enzymes. Similarly, the anti-inflammatory effect of API on important tryptophan metabolic enzymes was examined in lipopolysaccharide (LPS)-treated microglial cells.[Main methods] MG6 cells were exposed to LPS with or without API treatment for 24–48 h. IDO and ACMSD mRNA expression and production of inflammatory mediators were analyzed. Activation of inflammatory signaling pathways, such as mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB), was also examined to study the mechanism of API in the inflammatory state.[Key findings] LPS suppressed ACMSD expression and enhanced IDO expression. However, API elevated ACMSD mRNA expression and suppressed IDO mRNA expression in LPS-treated MG6 cells. Furthermore, API suppressed interleukin-6 and nitric oxide production, whereas overproduction of inflammatory mediators enhanced IDO expression and assisted tryptophan degradation. API also inhibited activation of extracellular signal-regulated kinase (Erk) and jun N-terminal kinase (JNK) MAPK, and degradation of IκBα.[Significance] These results indicate alteration of ACMSD expression under inflammatory conditions. Moreover, API recovers expression of tryptophan metabolic key enzymes, which may be mediated by inhibition of proinflammatory mediator production via inactivation of Erk, JNK MAPK, and NF-κB pathways in LPS-stimulated microglial cells.

Apigenin directly interacts with and inhibits topoisomerase 1 to upregulate CD26/DPP4 on colorectal carcinoma cells.

Introduction: CD26/dipeptidyl peptidase IV (DPP4) is a cell-surface glycoprotein present on most epithelial cells that modulates the local response to external signals. We have previously shown that the dietary flavone apigenin (4',5,7-trihydroxyflavone) upregulates cell-surface CD26/DPP4 on human colorectal carcinoma (CRC) cells and regulates its activities. We observed a unique synergistic interaction with the CRC chemotherapeutic agent irinotecan, which through its metabolite SN38 elevates CD26 at doses that are sub-cytotoxic. As SN38 interacts with topoisomerase 1 (Topo1) we evaluated whether apigenin influences Topo1 activity. Methods: We used a radioimmunoassay to selectively measure CD26 at the cell surface of HT-29 cells following various treatments. Topoisomerase 1 mRNA expression was measured by q-RT-PCR and protein abundance by western blot analysis. Direct inhibition of topoisomerase activity was measured using an assay of DNA supercoil relaxation with recombinant human Topo1. The role of Topo1 in the effect of apigenin was shown both pharmacologically and by siRNA silencing of Topo1. Molecular docking analysis was done with SBD computational software using the CDOCKER algorithm. Results: The interplay between apigenin and irinotecan was not observed when apigenin was combined with other chemotherapeutic drugs including the topoisomerase 2 inhibitors doxorubicin or etoposide. There was no enhancement of irinotecan action if apigenin was replaced with its hydroxylated metabolite luteolin (3',4',5,7-tetrahydroxyflavone) or emodin (6-methyl-1,3,8-trihydroxyanthraquinone), which is an inhibitor of the principal kinase target of apigenin, casein kinase 2 (CK2). Apigenin did not alter Topo1 mRNA expression, but siRNA knockdown of functional Topo1 eliminated the effect of apigenin and itself increased CD26 levels. Apigenin inhibited Topo1 activity in intact HT-29 cells and showed comparable inhibition of purified recombinant human Topo1 enzyme activity to that of SN-38, the active metabolite of irinotecan. Apigenin fits into the complex of Topo1 with DNA to directly inhibit Topo1 enzyme activity. Discussion: We conclude that apigenin has a unique fit into the Topo1-DNA functional complex that leads to direct inhibition of Topo1 activity, and suggest that this is the basis for the exceptional interaction with the CRC drug irinotecan. A combined action of these two agents may therefore exert a role to limit local signals that facilitate tumour progression.

Apigenin alleviates diabetic endothelial dysfunction through activating AMPK/PI3K/Akt/eNOS and Nrf2/HO‐1 signaling pathways

AbstractApigenin (4′,5,7‐trihydroxyflavone) is a natural flavone reported to present anti‐diabetic and anti‐oxidative bioactivities. The effect of apigenin to mitigate endothelial dysfunction in diabetes remains to be investigated. In the present study, the vaso‐protective effect of apigenin as well as its underlying action mechanisms was investigated using in vitro‐ and in vivo‐based assays. Aortas were detached from C57BL/6J mice for ex vivo treatment, and primary rat aortic endothelial cells (RAECs) were cultured and further stimulated using high glucose (HG) with or without apigenin. In‐vivo diabetic model was established by feeding male C57BL/6J mice with a high‐fat diet (60% kcal% fat) for a total of 14 weeks, whereas the treatment group was orally administered apigenin (25 mg/kg/day) during the last 4 weeks. Exposure to HG (30 mM, 48 h) impaired acetylcholine‐induced endothelium‐dependent relaxation (EDR) in mouse aortas and induced oxidative stress with the downregulation of adenosine 5'‐monophosphate (AMP)‐activated protein kinase (AMPK)/phosphatidyl inositol 3‐kinase (PI3K)/protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) and nuclear factor erythroid 2‐related factor 2 (Nrf2)/heme oxygenase 1 (HO‐1) signaling pathways in aortas and RAECs. These impairments were reversed by apigenin treatments. However, the vaso‐protective effects of apigenin were abolished by Compound C (AMPK inhibitor) and wortmannin (PI3K inhibitor). Chronic oral administration with apigenin ameliorated EDR and reduced oxidative stress in the aortas of high‐fat diet (HFD)‐induced obese and diabetic mice. In conclusion, this study revealed that apigenin improved endothelial function and suppressed oxidative stress in the vasculature in diabetes through the activation of AMPK/PI3K/Akt/eNOS and Nrf2/HO‐1 pathways, suggesting its therapeutic potential as a natural dietary flavonoid against vascular diseases associated with diabetes.

Apigenin remodels the gut microbiota to ameliorate ulcerative colitis.

Ulcerative colitis (UC), a chronic non-specific colorectal inflammatory disease with unclear etiology, has long plagued human health. Gut microbiota dysbiosis destroy homeostasis of the colon, which is closely related to ulcerative colitis progress. Apigenin, a flavonoid widely present in celery, has been found to improve ulcerative colitis. However, the potential molecular mechanism of apigenin ameliorating ulcerative colitis through protecting intestinal barrier and regulating gut microbiota remains undefined. Dextran sodium sulfate (DSS)-induced colitis mouse model was conducted to evaluate the effect of apigenin on UC. Disease activity index score of mice, colon tissue pathological, cytokines analysis, intestinal tight junction proteins expression, and colonic content short-chain fatty acids (SCFAs) and 16S rRNA gene sequencing were conducted to reflect the protection of apigenin on UC. The results indicated that apigenin significantly relieved the intestinal pathological injury, increased goblet cells quantity and mucin secretion, promoted anti-inflammatory cytokines IL-10 expression, and inhibited the expression of proinflammatory cytokines, TNF-α, IL-1β, IL-6 and MPO activity of colon tissue. Apigenin increased ZO-1, claudin-1 and occludin expressions to restore the integrity of the intestinal barrier. Moreover, apigenin remodeled the disordered gut microbiota by regulating the abundance of Akkermansia, Turicibacter, Klebsiella, Romboutsia, etc., and its metabolites (SCFAs), attenuating DSS-induced colon injury. We also investigated the effect of apigenin supplementation on potential metabolic pathways of gut microbiota. Apigenin effectively ameliorated DSS-induced UC via balancing gut microbiome to inhibit inflammation and protect gut barrier. With low toxicity and high efficiency, apigenin might serve as a potential therapeutic strategy for the treatment of UC via regulating the interaction and mechanism between host and microorganism.

Apigenin attenuates high-fat diet-induced nephropathy in rats by hypoglycemic and hypolipidemic effects, and concomitant activation of the Nrf2/antioxidant axis

• The protective potential of apigenin in rats with high-fat diet (HFD)-induced nephropathy by activation of Nrf2. • Apigenin reduced body weight. • Apigenin improved hyperglycemia, hyperinsulinemia, hyperlipidemia and renal tubular damage. • Apigenin increased the mRNA, cytoplasmic, and nuclear levels of Nrf2. • Apigenin reduced levels of GSH, SOD, CAT, MDA, TNF-α, IL-6. This study examined the protective potential of apigenin in rats with high-fat diet (HFD)-induced nephropathy, and tested its involvement in the activation of nuclear factor-erythroid 2 related factor 2 (Nrf2). Control, apigenin, HFD, HFD + apigenin, and HFD + Nrf2 inhibitor (brusatol) groups were formed. Apigenin was administered orally (50 mg/kg), and all treatments were conducted for 12 weeks. Apigenin, administered orally (50 mg/kg), significantly reduced body weight and reversed hyperglycemia, hyperinsulinemia, hyperlipidemia, renal tubular damage, and interstitial collagen deposition induced by HFD-fed rats. Additionally, apigenin significantly increased the mRNA, cytoplasmic, and nuclear levels of Nrf2 and levels of glutathione, superoxide dismutase, and catalase, but significantly reduced the levels of malondialdehyde, tumor necrosis factor-alpha, and interleukin-6, nuclear levels of nuclear factor kappa beta p65, and mRNA levels of transforming growth factor-β1, Bax, and caspase-3. Brusatol co-treatment abolished all the effects of apigenin on these markers, except for body and fat weights, glucose, and insulin. In conclusion, apigenin attenuated HFD-induced nephropathy by activating Nrf2.

LINC00629, a KLF10-responsive lncRNA, promotes the anticancer effects of apigenin by decreasing Mcl1 stability in oral squamous cell carcinoma.

Apigenin, a naturally occurring flavonoid, is known to exhibit antitumor activity in many cancers. However, the regulatory mechanism of apigenin and the long noncoding RNAs (lncRNAs) altered upon apigenin treatment in oral squamous cell carcinoma (OSCC) remain unclear. In this study, we found that LINC00629 was significantly upregulated in response to apigenin treatment. Upregulated LINC00629 enhanced the growth-suppressive and proapoptotic effects of apigenin on OSCC cells by interacting with Mcl1 and facilitating its degradation. Subsequently, our data indicated that KLF10, an important transcription factor, directly bound to the promoter of LINC00629, facilitating its transcription and contributing to apigenin-induced LINC00629 expression. Collectively, these results suggest that the KLF10-LINC00629-Mcl1 axis plays an important role in the anticancer effects of apigenin.

Quantum-mechanical characteristics of apigenin: Antiradical, metal chelation and inhibitory properties in physiologically relevant media

Density functional theory was used to examine the antioxidant activity of apigenin. All protonated species that are present in a non-negligible population at physiological pH were considered in the study. The ability to scavenge the hydroperoxide radical was evaluated in lipid and aqueous environments. The capacity to halt the Fenton reaction by chelating Fe(III) and Cu(II) ions was also investigated, as was the ability to inhibit xanthine oxidase. The results indicate that these activities may be particularly important in describing the beneficial effects of apigenin, especially because of its lower anti-•OOH potential than Trolox or vitamin C. The findings underscore the significant role of dianion in the antiradical and chelating properties, despite its presence in much lower molar fractions than other ions.